PT86093B - PROCESS FOR THE PREPARATION OF ACIDS 4-HYDROXY-4- (ALCENYL SUBSTITUTED) -CYCLOHEXANE-CARBOXYLIC ACIDS - Google Patents

Abstract

Compounds of the formula: <CHEM> wherein n is an integer from 0 to 2; R is straight-chain alkyl containing from 6 to 15 carbon atoms; X is hydrogen or, when n is 1 or 2, X can be -NH2; Y is hydroxy, -0- (C1-C4)alkyl, -NH2, -NH(C1-C4)alkyl , -N-(C1-C4)alkyl)2 or -NH-@@-COOH wherein R' is hydrogen, alkyl of 1 to 4 carbon atoms, or benzyl; and Z is hydroxy, -O-(C1-C4)alkyl), -NH2, -NH-(C1-C4)alkyl , or -N-(C1-C4)alkyl)2, can be used in pharmaceutical composition. They may be prepared by reacting <CHEM> with: HS-(CH2)n-@@-@-Y' f

Description

“PROCESS FOR THE PREPARATION OF 4-HYPROXY-4- ACIDS (AlCENIL ·

REPLACED) -ΟΙΟΡΟΗΕΧΑΝΟ-ΟΑΗΒΟΧίPICOS »

DESCRIPTIVE MEMORY

The present invention relates to a group of compounds that are 4-hydroxy-4- (substituted alkenyl) -cyclohexane-carboxylic acids and their acid derivatives. More particularly, the present invention relates to compounds of general formula:

HO

4-S- (CH ₂ ) _n I II

CH-C-Y

in which n represents an integer between 0 and 2; R represents a straight chain alkyl group having between 6 and 15 carbon atoms;

X represents a hydrogen atom or, when n represents the integer 1 or 2, X can represent a group -NH ₂ ; Y represents an oxygen atom or

-2 (a hydroxy group, (lower alkyl), -NH ₂ , -NH (lower alkyl) or -N- (lower alkyl) ₂ or a group of general formula -NH-CH-OOOH in which R * R 'represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms or a benzyl group, and Z represents a hydroxy group, -0- (lower alkyl), - NH ₂ , -NH- (lower alkyl) or - N- (lower alkyl) _2. Y and Z can be the same or different although they are usually the same The lower alkyl groups mentioned above contain between 1 and 4 carbon atoms.

Stereoisomerism with the present compounds is possible and the chemical structure as shown above is considered to encompass all stereoisomers and also the racemic mixtures of these stereoisomers. More specifically, when the substituent on the previous structure is attached to the cyclohexane ring by a single bond, there may be two isomers at each point depending on whether the substituent is above or below the plane of the cyclohexane ring. However, in the present compounds, with the substituents in positions 1 and 4 of the cyclohexane ring, a plane of symmetry is possible so that the number of possible stereoisomers is reduced. In the case of double bonding, geometric (cis-trans) isomerism is possible, according to the position of the group R in the double bonded structure relative to the remaining part of the molecule. Racemic mixtures can generally be obtained more quickly than individual optical isomers, so that the compounds described and obtained in the present invention

Convention should be considered as racemic mixtures unless otherwise indicated. When the absolute configuration is specified for a compound, it means the presence of the main optical isomer in a mixture that generally contains a small amount of the enantiomer.

The lower alkyl groups, as indicated above, contain between 1 and 4 carbon atoms and this same definition applies to any use of the term used below. Examples of such alkyl groups are methyl, ethyl, propyl and butyl groups. Examples of the alkyl groups represented by the symbol R are the groups octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl.

Therapeutically acceptable salts of the foregoing acids, that is, in which the symbols Y and / or Z represent a hydroxy group are also included within the scope of the present invention. These alkaline salts include, but are not limited to, sodium, potassium, calcium, magnesium, triethylamine, tromethamine, dicyclohexylamine and the like, as is well known to those skilled in the art. These alkaline salts can be obtained by standard processes using the free acids of the present invention and the appropriate base. The preferred compounds of the present invention are, however, those in which the symbols Y and Z both represent hydroxy groups.

Examples of compounds of the present invention are the following compounds:

Z4 (R) -Z'10, 4,4, 4 (Z) 77-4-zfl-zf (2-carboxyethyl) -io_7 "2-hexadecenyl _ / - 4-hydroxycyclohexanecarboxylic acid.

Z'4 (R) -Z'4 «, 4p, 4 (Z) .7 _ / - 4-Z” 1Z ~ (carboxymethyl) -thio_7-2-hexadecenyl 7 ^Z -4-hydroxycyelohexane-carboxylic acid.

Z'4 (R) -ZM, 4 ^, 4 (Z) 7 / -4-Z 1-7 (2-oarboxyethyl) -thio_7-2-octadeoenyl_7-4-hydroxycyclohexanecarboxylic acid.

Z74 (R) -Z1cí, 4f, 4 (Z) J (2-carboxyethyl) -thio__Z-2-tetradecenyl 7-4-hydroxycyclohexanecarboxylic acid, 74 (R) -71 ° m 4p, 4 (Z) J 1 -7 (carbamoyl methyl) -thioJ7-2-hexadecenyl7-4-hydroxycyclohexanecarboxylic.

Z74 (R) -Z'1,4,4,4 (4) 77-4-71 ~ 7 (3-oarboxypropyl) -thioJ7-2-hexadecenyl_7-4-hydroxycyclohexanecarboxylic acid.

Z74 (R) -Z ~ 1 ^, 4p, 4 (Z) _7_7-4-ZTl-Z ^- ( ² -amino-2-carboxyethyl) -i; io_7- ² ~ b. 7 ”4-hydroxycyclohexanocarboxylic acid .

Z ^ 4 (R) -71 * »4 ^, 4 (Z) 77-4-71-7Zfl-oarboxymethyl) -carbamoylmethylJ7-thio _7-2-hexadecenyl_7-4-hydroxycyclohexanecarboxylic acid.

7 4 (R) -71 *> 4 ^, 4 (Z) 77-4-71-77 ^ - (1-oarboxybutyl) ~ carbamoylniethyl_7-thio _7_2-hexadecenyl_7-4-hydroxycyclohexane-carboxylic acid.

acid Z "4 (R) -Z'1 ° ^i, 4?, 4 (Z) 77-4-71-77 ^ - (1-carboxy-2-phenylethyl) -carbamoilmetil7'ti-7 ^7-2 “^ ^Iexa ^ ecenil7 ^_ 4-hydroxycolohexanecarboxylic.

Z ^ 4 (R) -Z ~ 1 ^> 4p, 4 (Z) 4-7J-L-Z 7carbamoilmetil) -tio7 ^"2" d ^ ^{exa ecen} il7-4-hydroxycyclohexane-carboxamide.

Z-4 (R) -tC1 ^0I »4j ₃ & 4 ^(Z) - / - / - 4-71 - / ^ (N-methylcarbamoyl methyl) -tio_ /" -h ^{2 exa OAE-hydroxy-N} nil._Z4 -niethylcyclohexane-car boxamide.

74 (R) -Z1 * »4p, 4 (Z) 77-4-71-7 (N, N-diethylcarb-

moilmethyl) -thio _7-2-hexadecenyl _7-4-hydroxy-N, N-diethylcyclohexane-carboxamide.

Z * 4 (R) -Z ~ 1 ^, 4 <V, 4 (Z) _7_7 ~ 4-Z 1- / 2-earboxyethyl) -thio_7-2-hexadecenyl__7-4-hydroxycyclohexane-carboxylic acid.

// 4 (R) - / 1 ^, 4¾ 4 (Z) // - 4-Z 1-Z (2-carboxyethyl) -thio_7-2-hexadecenyl / ⁷ ”4-hydroxycyclohexane-carboxylic.

Z4 (s) - // 1 ^, 4 #, 4 ^) // 7-4- / 1- / ^- (2-carboxyethyl) -thio / -2-hexadecenyl / -4-hyoxoxycyclohexane-carboxylic acid.

/ 1 &, 4¾ 4 (Z) / - (-) - 4- / 1- / ~ (2-carboxyethyl) -thio _Z-2-hexadecenyl / -4-hydroxycyclohexane-carboxylic acid.

acid / 1¾ 4p, 4 (Z) _- 7- (Í) -4-Z * 1 ~ / ”(2-carboxymethyl)

-tio / -2-hexadecenyl / -4-hydroxycyclohexane-carboxylic. / ^ 1¾ 4p, 4 (E) ./- (-) - 4-Z ”1 - / (2-carboxyethyl) -thio / -2-hexadeeenyl / -4-hydroxycyclohexane-carboxylic acid. / ”4 (S) - / 1¾ 4p, 4 (E) JJ-4 - // 1- / 7 (carboxymethyl) -thio / ^z -2-hexadecenyl / -4-hydroxycyclohexane-carboxylic acid.

The compounds of the present invention are prepared by reacting an epoxide of general formula

H C-Z '

in which R has the meaning defined above and Z 'represents a group -0- (lower alkyl), -NHg' -NH (lower alkyl) or -N- (lower alkyl) ₂ with a derivative of the mercapto-alkanoic acid of formula general

Σ '0

HS- (CH ₂ ) _n -CH-CY 'in which n represents an integer between 0 and 2; Σ 'represents a hydrogen atom or, when n represents the integer 1 or 2, Σ' can represent a group of general formula Q-NH-, in which Q represents an amine protective group; Y 'represents a group -0- (lower alkyl), -NH ₂ , -NH (lower alkyl), -N- (lower alkyl) ₂ R' 0 ¹ ”or -NH-CH-CY in which R 'represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms or a benzyl group and Y represents the -0- (lower alkyl) group;

in an appropriate solvent, in the presence of a base, followed eventually when Y ', Y or Z' represent a -0- (lower alkyl) group, treatment with a strong inorganic base, followed by acidification with a strong acid to obtain compounds in whose general formula the Y, Y or Z symbols represent an -OH group. Although Y 'and Z' are usually the same in the previous reagents, they do not have to be the same which is partly convenient for introducing differences in the acid functions involved by the appropriate choice of reagents. Obviously, when one of the groups represented

ροτ Υ ’and Ζ 'in the product is an ester / ie, -0- (lower alkyl) this group can be further hydrolyzed by standard processes to obtain the corresponding carboxylic acid free group.

Although, when Σ represents a -NH ₂ group, a protecting group is not specifically needed, the amine group can be protected by one of the standard protecting groups for amino acids. The trifluoroacetyl group is a preferred group for this purpose since it hydrolyzes at the same time as any of the ester groups represented by the symbols Y or Z eliminating a free amino group. The benzyloxycarbonyl group is also an effective protecting group although the conditions necessary for hydrolysis are more stringent than those required for a trifluoroacetyl group. However, the benzyloxycarbon group can also be eliminated by catalytic hydrogenation without affecting any ester group present elsewhere in the molecule.

The base used in the initial treatment of the epoxide is preferably a tertiary amine such as triethylamine. The solvent used in the reaction must dissolve the reagents but must be inert to the reaction. Lower alkanols are preferred solvents and, particularly, lower alkanols which correspond to the alcohol portion of any ester used in the reaction. In this way, methanol would be used in the case of methyl esters, while ethanol should be used in the case of ethyl esters.

The subsequent saponification of the esters with a strong base, followed by acidification of the resulting salt mixture, to obtain the corresponding free acid, corresponds to

standard processes in organic chemistry so that it will not be necessary to explain the reagents and reaction conditions used.

Epoxides used as starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. In this way, methyl 4-hydroxybenzoate is hydrogenated using 5% sodium on alumina as a catalyst to obtain methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate to methyl 4-oxocyclohexanecarboxylate. The homologation of carbon 2 of methyl 4-oxocyclohexanecarboxylate to obtain methyl 4- (oxoethylidene) -cylohexanocarboxylate is carried out using the method developed by A.I. Meyers. Acetaldehyde t-butylimine is treated with metal using lithium diisopropylamide and then treated with diethyl chlorophosphate to obtain lithium amino phosphonate. The addition of methyl 4-oxocyclohexane-carboxylate and the subsequent acid hydrolysis provides methyl 4- (oxoethylidene) -cyclohexyl-carboxylate. The reduction of this oxoethylidene compound with sodium borohydride, provides methyl 4- (2-hydroxyethylidene) -cyclohexanecarboxylate.

The conversion of the hydroxyethylidene compound to the desired intermediate epoxide can be illustrated by the following series of reactions:

ί

More specifically, chirality is introduced at this point in the synthetic process, using the known technique of asymmetric Sharpless epoxidation, by which the hydroxyethylidene compound is treated, for example, with (+) - diethyl tartrate, titanium isopropoxide (IV ) and titanium (IV) t-butylhydroperoxide, producing two diastereomers, 2- (hydroximethyl-ζΓ3- (S) -cis or trans_7 ~ l- ~ ^oxas OI ^r o Z ~ ² · 5Z-octane-o- carboxylate methyl: The cis form of the indicated compound is oxidized using the known Swern oxidation technique, using oxalyl chloride, dimethylsulfoxide and triethylamine

-10 to produce methyl 2-formyl- / 3 (S) -cis_7-1-oxasyr> 2,5,7-octane-6-carboxylate. Wittig's olefin from this compound, using an alkyltriphenylphosphonium bromide and potassium t-butoxide provides a 3 (S) -Z 3 #, 3 (Z), 6oi_7_7-l-oxaspiro /*2.5_7-octane-6-carboxylate methyl. The use of (-) - (-) - diethyl tartrate in the epoxidation process mentioned above, provides the other two isomers of the compound of 2- (hydroxymethyl), which are then reacted, as described above, to obtain the isomers 3 (R) ·

In the examples where the desired end product is an amide, these compounds can be obtained using the appropriate reagents in the processes described above. Alternatively, the esters of the present invention, obtained as described above, can be converted to the corresponding amides by reaction with ammonia or an appropriate amine.

The following examples describe in more detail specific conditions used in the processes mentioned above.

The compounds of the present invention are effective in the treatment of allergic diseases and particularly in the treatment of bronchial asthma. In this way, SRS-A (slow-reacting anaphylase substance) is known as a substance that is a very important mediator in allergic bronchial asthma. Specifically, SRS-A is a substance that is synthesized and released in or near target tissues, in a sensitive allergic individual, after abrupt provocation by the appropriate antigen, with human bronchi being particularly sensitive to SRS-A. In this way, the substance that can react against

effects of SRS-A will be effective in the treatment of bronchial asthma.

More recent studies have established that SRS-A is actually a mixture of substances that can be described as peptide-leuootrienes. LTD ^ ® is one of these leukotrienes and can be considered as representative of them, in such a way that the antagonism of this specific substance will generally cause effects similar to the antagonism of SRS-A ,. The compounds of the present invention are specifically effective as LTD4 antagonists, in such a way that they are effective in the treatment of allergic diseases and particularly in the treatment of bronchial asthma. The present compounds are selected for this antagonistic activity so that they are not considered to be competitive against histamine or carbacol.

The activity of the compounds of the present invention can be demonstrated by the following test procedures.

Longitudinal muscle of guinea pig ileum

Male guinea pigs, Hartley-Duncan were sacrificed by cervical dislocation. The terminal portion of the ileum was removed, washed and placed in a Burn-modified Tyrode solution. The longitudinal muscle was carefully dissected from the ileum muscle. The longitudinal muscle was cut into 1-2 cm segments, which were placed in a tissue bath containing an oxygenated Burn modified Tyrode solution and heated to 37 ° C. A strain of 1.0 gram was then applied to each muscle segment. After equilibration for 1 hour, 1 µl of indomethacin was added to each bath. After 5 minutes, each tissue segment was exposed to a concentration of 60 nM leukotriene D4. This response was considered

-12 <ζ as the initial maximum contraction that each segment would produce. After washing the tissue several times over a period of 1 hour, an additional 1 µM of indomethacin was added to each bath. After a period of 5 minutes, the test agent or vehicle was added to the bath. After 15 minutes, a concentration-response curve was drawn using, cumulatively, the increasing concentrations of leukotriene D4. The response-concentration was then compared with the initial maximum contraction. An active test compound was considered, when for a concentration up to 100 µM there was a significant shift to the right of the concentration-response relationship for leukotriene D4. Antagonist activity was quantified in terms of a pAg value calculated according to the method described by Arunlakshana and Schild, (Brit. J. Pharmac. Chemotherap ' ^1. , 14; 1959 p. 48.

3H-LTD4 - Specific receptor that links lung membranes in guinea pigs

Male guinea pigs were sacrificed and the lungs were removed by placing them in 50 mM ice-cold 50 mM Tris-HCl solutions with a pH of 7.4. The lungs were then homogenized with a Polytron homogenizer and the homogenized substance was centrifuged for 1000 gr for 10 minutes at 4 C. Two parts were centrifuged at 30000 gr r> or 15 minutes at 4 G to obtain the nasi membrane membrane. This tablet was resuspended in 50 mM Tris-HCl to provide the stirred suspension of lung membranes. Two tests were carried out

ligation in a 50 mM Tris-HCl solution at 7 »6 r> H and at a temperature of 37 ° C during incubation periods of 20 to 40 minutes. The separation of ^ H-LTD ^ bound to the free ³ H-LTD ^ was carried out by rapid vacuum filtration through Whatman's GF / B glass fiber filters using an ice-cold Tris-HCl buffer solution and three 4 ml washes. Filtration and washing was completed in less than 8 seconds. The radioactivity in the filters was then measured. The specific binding of ^ H-LTD ^ was defined as the binding of ³ H-LTD ^ in the absence of unlabeled LTB ^ minus the binding of ^ H-BTD ^ in the presence of unmarked LTD ^ 2x10 ”. The specific ³ H-1TD bond was 60 to 80% of the total bond. Studies with test agents demonstrate the ability of the rare test compound to inhibit specific binding of ³ H-BTB2. In these assays, increasing concentrations of the agent are used to block specific binding of ³ H-LTB2. The concentration that reduces the specific binding of ^3% H-1TD ^ to 50% is called ΙΟ ^ θ.

The specific activity observed for some with compounds of the present invention when tested in the processes described above is summarized in the following table. However, variations in activity occur and activity appears to decrease with decreasing length of the R-alkyl groups of the tetradecylidene compounds included in the table.

COMPOUND (Example ^Nos.) ILEO GP pA ₂ (LTD ₄ ) LUNG GP Specific connection IC ₅₀ , 10D 9.8 10H 9.61 8.7 10F 9.42 - 11 7.87 - 10J 8.26 7.1 10L 8.57 8.0

Biological activity in Vivo

The compounds of the present invention were also tested for leukotriene antagonist activity in anesthetized guinea pigs using a modified Konzett-Rossler preparation. Guinea pigs were anesthetized specifically with sodium pentobarbital and surgically prepared for artificial ventilation through a constant volume respiratory filter. The air pressure produced by the respiratory filter for each insufflation of the guinea pigs' lungs was measured. Increases in air pressure above a baseline are indicative of bronchoconstriction. After establishing a baseline for inflated air pressure, bronchoconstriction was induced by an intravenous injection with 50 or 100 ng / kg of leukotriene D2. This response was considered the initial response. After the inflated air pressure returned to the baseline, the guinea pig was treated with the desired dosage of the test compound or the carrier substance, intravenously (iv) or intraduodenal (id) and injected again with leukotriene for 1 minute

-15C χ / / «(after i.v. administration) or 5 and 20 minutes (after i.d. administration). This response was then compared to the initial response and the inhibition of the response determined. The results can be summarized as follows, with inhibition values provided for i.d. the largest of the two results obtained.

COMPOUND (Example N ^2. )

% INHIBITION

DOSE

VIA

10F 0.0002 mg / kg i.v. 38 10? 0.002 mg / kg i.v. 52 10F 0.02 mg / kg i.v. 94 101 * 0.1 mg / kg i.d. 74 10F 0.2 mg / kg i.d. 93 10J 0.5 mg / kg i.d. 48 10J 1.0 mg / kg i.d. 53 101 0.05 mg / kg i.v. 19 101 0.5 mg / kg i.v. 74 101 1.0 mg / kg i.d. 25

The compounds of the present invention must be administered as individual therapeutic agents as well as in mixtures with other therapeutic agents. They can be administered alone although they are administered in the form of pharmaceutical compositions, that is, mixtures of the active agents with pharmaceutically appropriate vehicles or diluents. Examples of such compositions include tablets, lozenges, capsules, powders, aerosol atomizers, aqueous or oily suspensions, syrups, elixirs and aqueous solutions for injections. The compounds are preferably administered in the form of an oral dosage.

The nature of the pharmaceutical composition and the diluent or pharmaceutical carrier, will certainly depend on the desired route of administration, i.e., orally, narenteric or by inhalation. Oral compositions may exist in the form of tablets or capsules and may contain conventional excinients such as binding agents (for example, syrups, acacia, gelatin, sorbitol, tragacanth or polyvinylnirrolidone), fillers (for example, lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycine), lubricants (eg magnesium stearate, talc, nolethylene glycol or silica), disintegrating agents (eg starch) or wetting agents (eg lauryl sulphate and sodium). Liquid oral preparations can exist in the form of aqueous or oily suspensions, solutions, emulsions, shampoo, elixirs, etc. or they may be in the form of a dry product for reconstitution with water or other suitable vehicles before use. Such liquid pressings may contain conventional additives, such as suspending agents, flavoring agents, diluents or emulsifying agents. For narenteric administration or inhalation, solutions or suspensions of a compound of the present invention can be used with conventional pharmaceutical vehicles, for example, with an aerosol spray for inhalation, an aqueous solution for intravenous injection or an oil suspension for intramuscular injection. . The compounds can also be administered via inhalers or other devices that allow the active compounds, in the form of dry knots, to come into direct contact with the lungs. Processes for preparing compositions, as described above, are described in standard texts, such as Remingto's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsyl vania.

The compounds of the present invention or the respective pharmaceutical compositions can be administered to asthmatic patients at dosages ranging from about 0.1 to about 40 mg / kg. Single oral doses of approximately 0.1-1000 mg of active ingredient and multiple oral doses amounting to about 4000 mg / day of active ingredient can be used.

When administered by inhalation, the lowest doses are generally given, that is, in the order of about 0.1 of the normal dosage for the particular compound in question. These values are only illustrative and the doctor will certainly determine, at the time, the most appropriate dosage, for a given patient based on factors such as age, weight, diagnosis, severity of symptoms and the particular agent to be administered.

The following examples are presented to illustrate the present invention although they are not intended to be in any way limiting.

EXAMPLE 1

A bottle of Parr was loaded with 150 ml of methanol and 25 g of methyl 4-hydroxybenzoate was added. Then the bottle was filled with nitrogen, 2.5 g of sodium on 5% alumina was added and the reaction mixture was pressurized under a hydrogen stream at 3.74 atmospheres for 18 hours.

-18 / hours, with constant agitation. The reaction mixture was pressure washed with nitrogen and filtered through diatomaceous earth to remove the catalyst. The day soil was washed with methanol taking care not to filter the catalyst until dry. The filtrates were combined and methanol was removed under reduced pressure with very gentle heating (ca. 40 ° C). The product residue and alumina were treated with 200 ml of ether to which 3 g of anhydrous potassium carbonate were added. Precipitated alumina and potassium carbonate were filtered off through diatomaceous earth. The filtrates were then washed with ether, combined and the solvent was removed under reduced pressure to obtain the crude product. Then, ampoule-to-ampoule distillation was performed in the Kugelrohr equipment at 80 ° -100 ° C / ca. 1 mm to obtain 25.0 g (98%) of methyl 4-hydroxycyclohexane-carboxylate. NMR (CDCl3, 60 MHz) - 3.85 (s, 1 H); 3.65 (s, 3 H); 2.50-1.20 (m, 10 H).

EXAMPLE 2

24 g of Celite dry non-formaldehyde, 11.4 g of sodium acetate and 90.5 g of pyridinium chlorooromato were added to the 400 ml of anhydrous dichloromethane. An additional 350 ml of methylene chloride was added followed by the addition, via a syringe, of 44.5 g of methyl 4-hydroxycyclohexanecarboxylate in 40 ml of dichloromethane. After 3.5 hours, 800 ml of ether was added with stirring and the mixture was suction filtered through 250 g of silica gel, then the solid was washed 4 times with ether. The combined filtrates were concentrated until a green oil was obtained, which was treated with 150 ml of

-19 ether and filtered again through 50 g of silica gel and the silica gel was washed with ether. The combined filtrates were concentrated until a clear oil was obtained which was distilled in a Kugelrohr equipment at 65-85 C / ca. 1 mm to obtain 42.6 g (97.5%) of methyl 4-oxocyclohexanecarboxylate. ¹ H NMR (CDCl ₃ , 60 MHz) S 3.70 (s, 3H); 2.9-1.8 (9 H).

EXAMPLE 3

A mixture of 729 ml of anhydrous tetrahydrofuran and 76.4 ml of anhydrous diisopropylamine was cooled to 3 ° C in an ice-water bath. Then, drop by drop,

340.6 ml of n-butyllithium in hexane for 45 minutes, followed by another 15 minutes of stirring. The solution was then cooled to -75 ° C and 26.9 g of acetaldehyde t-butylimine was added dropwise with a syringe over 20 minutes, followed by another 30 minutes of stirring. With the temperature still at -75 ° C, 47.0 g of diethyl chlorophosphate was added with a dropping funnel over 1 hour. The reaction mixture was stirred for an additional hour at -75 ° C, heated to -11 ° C for 2 hours and cooled again to -75 ° C. Then, 28.4 g of methyl 4-oxocyclohexanecarboxylate in 50 ml of tetrahydrofuran were added over 1 hour with a greasing funnel. The reaction mixture was allowed to warm up overnight to room temperature. It was then poured into a mixture of 49.0 g of oxalic acid in 1.8 liters of water and

1.8 l of toluene. The mixture was then stirred vigorously for 24 hours and the aqueous layer was separated and extracted with ether (2x500 ml). The combined toluene and ether extracts were washed with 5% aqueous oxalic acid (2x500 ml), 500 ml of saturated sodium bicarbonate and 500 ml of saturated sodium chloride. Dried /

then the organic layer over anhydrous potassium carbonate, filtered and concentrated in vacuo. The resulting oil was purified in the Prep LC (25% ethyl acetate / hexane, 300 ml / min / min, 2 min / cm, 2 columns, R ^ = 7.5 min) to obtain

18.5 g of methyl 4- (oxo-ethylidene) -cyolohexanecarboxylate.

NMR (60 MHz CDClp) b 10.05 (d, 1 H); 5.85 (d, 1 H); 3.70 (s, 3 H); 2.8-1.5 (9 H).

EXAMPLE 4

A solution was prepared from 77 ml of methanol and 13.0 g of methyl 4- (oxoethylidene) -cyclohexanecarboxylate and cooled to 3 ° C with an ice water bath. Sodium borohydride (3.1 g) was added portionwise with vigorous stirring over 30 minutes. The reaction was stirred for an additional 1 hour at 3 ° C before glacial acetic acid (1 ml) was added to end the reaction and the methanol was removed under reduced pressure. The residue was added to 200 ml of dichloromethane and divided into portions with 400 ml of water. The organic layer was separated and washed with 200 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified in the Prep LC (30% ethyl acetate / hexane, 250 ml / min., 2 min./cm, 2 columns, = 13 min.) To obtain 11.5 g of product weakly pure. Ampoule-to-ampoule distillation in Kugelrohr equipment at 150 ° -16 ° C / O, 8 mm gave 9.03 g (69%) of methyl 4- (2-hydroxyethylidene) -cyclohexanecarboxylate. NMR (CD01 _3, 60 MHz) S 5.40 (t, 1H); 4.10 (d, 2 H); 3.70 (s, 3 H); 2.9-1.3 (10 H).

-21 /

EXAMPLE 5

To 300 ml of anhydrous dioloromethane, cooled to -25 ° 0 to -30 ° C in a dry ice / acetone bath, 12.9 ml of titanium (IV) isopropoxide was added with a syringe with stirring and a solution of 8.9 ml of (+) - diethyl tartrate in 10 ml of dioloromethane. After 10 minutes, 8.0 g of methyl 4- (2-hydroxyethylidene) -cyclohexanecarboxylate in 20 ml of dichloromethane were added to the reaction mixture, followed by washing the flask and syringe with 20 ml of dichloromethane. Then, 18.4 ml of 4.7 M t-butylhydroxide in toluene was immediately added. The reaction flask was then transferred to a freezer and left to stand at -20 ° C for 24 hours. The reaction mixture was then suction filtered through silica gel, which was washed with 500 ml of 25% ethyl acetate / dichloromethane. The combined filtrates were concentrated in vacuo to obtain a yellow oil. Thin layer chromatography (20% ethyl acetate / hexane) of the crude mixture indicated that the syn and anti diastereomers were separable by chromatography with Rf sin = 0.14 and Rf anti = 0.17. Separated in Prep LC (10% isopropanol / hexane, 250 ml / min., 2 min./cm, 2 columns, ⁼ 16 min., R sin sin = 23 min.) To obtain 2.7 g of anti epoxide and 2.5 g sin epoxide in the form of oils. The sin epoxide was recrystallized twice from 3% ether / nentane to obtain 0.41 g of 2- (hydroxymethyl) -Z ~ 3 (S) -cis_7-l-oxaspiro /~2.5_7-octane Methyl-6-carboxylate, in the form of long, flat, white crystals melted at 67 ° -68 ° C; Z / 7p ° -13.3 ° (c 1.15, chloroform); % ee =.> 95%

-22 / (X The anti-epoxide was recrystallized twice in ether / '/ / pentane at 3θ% to obtain 0.57 g of white crystals, with flat, flat, melting at 31 ° -33 ° C; Α7ρ ° -10.6 ^ο (c 1.22, chloroform);% ee = 80%. NMR for epoxide sin (CDCl ^, 300 MHz) S 3.80 (m, 2 H); 3.70 (s, 3 H); 3.10 (dd, 1 H); 2.00-1.40 (9 H).

Example 6

A mixture of 27 ml of anhydrous dichloromethane and 0.20 ml of oxalyl chloride was prepared. The mixture was cooled to -75 ° C and 0.35 ml of dimethyl sulfoxide was added dropwise over 5 minutes with stirring. 3 & 1 mg of 2- (hydroxymethyl) - // 3 (S) -ois 7-1-oxaspiro / 72 were added dropwise to the reaction mixture over 10 minutes. b._7octane-6-car methyl boxylate in 3 ml of dichloromethane. After 20 minutes of stirring, 1.45 ml of triethylamine was added dropwise over 5 minutes. The reaction mixture was then allowed to warm to room temperature over 45 minutes and the solvent was removed under reduced pressure. The white solid residue was added to 50 ml of ether and filtered through an agglomerated glass funnel. The filtrate was concentrated in vacuo to produce a yellow oil. This crude material was purified on Prep LC (20% ethyl acetate / hexane, 250 ml / min., 2 min./cm, 1 column, R ^ = 4.75 min.) To obtain

355.5 mg methyl 2-formyl- / 3 (S) -cisγ-1-oxaspiro / 72.5_7-octane-6-carboxylate in the form of an oil / õó / p +132.0 (c 0, 71, chloroform). ^X H NMR (CDG1, 300 MHz) S 9.50 (d, 1 H);

3.70 (s, 3H); 3.20 (d, 1H); 2.60-1.30 (9 H).

-23 / '• y EXAMPLE 7 ‘*

To 20 ml of anhydrous tetrahydrofuran, 1.80 g of n-tetradecyltriphenylphosphonium bromide was added with stirring. Then, 6.4 ml of 0.5 M potassium t-butoxy in tetrahydrofuran was added dropwise causing the solution to change to orange. After 5 minutes, the reaction mixture was added dropwise to 342 mg of 2-formyl-Z3 (S) -cis_7-1-oxaspiro / ”2,5_7-octane-6-carboxylate in 3 ml of tetrahydrofuran by varying the solution to light yellow. Six more 0.5 ml portions of the potassium t-butoxide solution were then added at 10 minute intervals, leading the reaction to completion. Then, 5 ml of water was added and the reaction mixture was poured into 200 ml of ether. The mixture was washed with saturated sodium chloride (2x100 ml) and concentrated in vacuo to 100 ml. Then, 900 ml of hexane was added and the cloudy solution was suction filtered through silica gel which was washed with 500 ml of 10% ether / hexane. The combined filtrates were concentrated in vacuo to produce a yellow oil which was purified on Prep LC (5% ethyl acetate / hexane, 250 ml / min., 2 min./cm, 1 column, R3 = 5 min. ) to obtain 527 mg of 2- (l-pentadecenyl) -Z ~ 3 (5) - // 3 ⁰ ¼ 3 ( ^z ), Ço / T / Zl-oxaspiro // 2,5 ^ Z-octano-6 -methyl carboxylate in the form of an oil.

/ 3rd / 20 _{+ 25 ,? Oj92>} oxoropharmium). ^X h NMR (CBC1 ³ , 300 MHz)

S 5.75 (m, 1 H); 5.25 (t, 1 H); 3.70 (s, 3 H); 3.45 (d, 1 H); 2.45-1.20 (34 H).

The process of example 5 was repeated using (-) - diethyl tartrate to obtain the other two compounds

spiro and these compounds, together with the anti-ob compound

taken in example 5, each reacted according to the procedures described in examples 6 and 7 described above. In addition, the process of example 7, described above, was also repeated using octltriphenylphosphonium bromide instead of tetradecyltriphenylphosphonium bromide. The products obtained in this way were the following:

2- (1-pentadecenyl) -Z 3 (S) - / 3ps 3 (Z), _7-1-oxas pyro 7 * 2.5V “° ^{c- to} no-6-carboxylate.

Methyl 2- (1-pentadecenyl) -Z * 3 (R) -Zr 3, 6, 3 (Z), 6 <* -_ 7J ^ -l-oxas, 5_7-octane-6-carboxylate.

2- (1-pentadecenyl) -Z73 (R) -Z73 ^, 3 (Z), 6'^ 7_7-1-oxaspiro / ”2,5_7-octane-6-carboxylate.

2- (l-nonenyl) - / 3 (S) -Z'34C _? Methyl 3 (Z), 6'/ ^ / - 1-oxaspiro-772,5_T-octane-6-carboxylate.

EXAMPLE 8

To a mixture of 227 mg of 2- (lr) entadecenyl) -Z ~ 3 (S) -Z3 ° o, 3 (Z), ^ 7-1-oxaspiro 7 ^ 2,5_7-octane-6-carboxylate in 2.7 ml of methanol, 0.28 ml of triethylamine was added with stirring followed by the addition of 0.20 ml of methyl 3-mercaptopropionate. After 24 hours, methanol was removed under reduced pressure and the oil was added to 100 ml of ether. The mixture was then washed with 50 ml of 0.5N hydrochloric acid and 50 ml of saturated sodium chloride. Then it was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a yellow oil. Then the oil was purified in Prep LC (10% ethyl acetate / hexane, 250 ml / min., 2 min./cm, 1 column, R ^ = 22 min.) To obtain

-25 /

278.4 mg // 4 (R) -Z 1 ° ^, 4 ° ^, 4 (Z) J J-4-hydroxy-4-Z 1 ~ Z '(2- ^z -carbomethoxyethyl) -tio_7- Methyl 2-hexadecenylV-cyclohexanecarboxylate in the form of an oil. Ζ ^ Ζρθ + 33.5 ⁰ (c 0.88, chloroform). ^Χ Η NMR (CDCly 300 MHz) E 5.60 (m, 1 H); 5.4 (t, 1 H); 3.70 (s, 3 H); 3.65 (s, 3 H)? 3.60 (d, 1 H) *, 2.75 (m, 2 H); 2.60 (m, 2 H); 2.20-1.20 (34 H); 0.89 (t, 3 H).

EXAMPLE 9

A solution of Z ”4 (R) -Z 4 ^, 4 (Z) _7_7-4-hydroxy-4 - // 1Z ~ (2-carbomethoxyethyl) -thio- ⁷ -2-hexadecenylJ ^z -cyclohexanecarboxylate was dissolved in 4.0 ml of absolute ethanol. Then, 340 mg of potassium hydroxide tablets in 3.3 ml of water were added to the cloudy solution with stirring. After 4.5 hours, the clear solution was diluted with 75 ml of water. The aqueous mixture was washed with 75 ml of ether and then acidified with 15 ml of 0.5N hydrochloric acid. The aqueous mixture was then extracted with ethyl acetate (3x150 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain an off-white solid. This solid was recrystallized from 10% ether / hexane to obtain 157 mg (64%) of Z ~ 4 (R) -ZI ^o4 , 4 «-, 4 (Z) JZ7" 4-Z 1 acid - / 7 (2-carboxyethyl) -tio_7 ” ² “ hexadecenyl _ / - 4-hydroxycyclohexane-carboxylic, in the form of a clean white knot melting at 121 ° -123 ° 0; Z ^ _ / p ° + 32.0 ° (e 0.95, chloroform). NMR (CDCly 300 MHz) 5.62 (m, 1 H); 5.40 (t, 1 H);

3.62 (d, 1 H); 2.74 (m, 2 H); 2.62 (m, 2 H); 2.25-1.20 (34 H); 0.89 (t, 3 H). This compound has the following structural formula

H COOH

CH-S-CH _o CH _o C00H \ ^{2 2}

CH

II

EXAMPLES 1OA - 1OM

When the appropriate oxaspiro and mercapto compounds react, according to the process described in example 8, and the resulting esters are saponified, as described in example 9, the following compounds are obtained:

A. Z ”4 (S) -Z1 ^, 4 34.4 (Z) _7J <-4-Zl-Z; (2-carboxyethyl) -thio _ / - 2-bexadecenyl _ / - 4-hydroxycyclohexanecarboxylic acid melting at 122 ° -123 ° C; ^2O -38.1 ° (c 0.89, clorofo'rmio).

^X H NMR (CDClp 300 MHz) â € 5.61 (m, 1 H); 5.39 (t, 1 H); 3.62 (d, 1 H); 2.68 (m, 4 H); 2.23-1.22 (33 H); 0.88 (t, 3 H).

B. acid / 74 (R) -Zíx, 4?, 4 (Z) -4-zf'l _7J ⁷ Z ~ (carboxymethyl) -tiq / hexade cecenil _-2-t _ / - hydroxy-4-carboxylic hexane cycle lic-cj Z ”° <Jp ^O +23.9 ⁰ (c 0.66, chloroform). ^{* X} H NMR (CDCly 300 MHz) (5 5.69 (m, 1 H); 5.39 (t, 1H), · 3.82 (d, 1 H); 3.21 (m, 2 h) j 2.30-1.20 (33 H); 0.88 (t, 3H).

C. /24(3)-/^.4^,4(Z)_7_7-4-/Cl-Z'(carboximetil)-tio_/2-h.exadecenyl _ / - 4-h.hydroxycyclohexanecarboxylic acid;

Μ ρ ^Ο -11.5 ° (c 1.42, chloroform). ^Χ Η NMR (CDClj, 300 MHz)

5.66 (m, 1 H); 5.37 (m, 1H); 3.82 (d, 1H); 3.22 (m, 2 H); 2.10-1.12 (33 H); 0.88 (t, 3 H).

D. / 4 (R) -71 ° G 4, 4 (Z) 77-4-Z1- (carboxymethyl) thio 7-2-hexadecenyl 7-4-hydroxycyclohexanecarboxylic acid;

7 ^ 7p ° + 3.3 ° (c 0.73, chloroform). ¹ H NMR (CDClp 300 MHz) 5.75 (m, 1H); 5.44 (m, 1 H); 4.26 (d, 1 H); 3.20 (m, 2 H); 2.40-1.18 (33 H); 0.88 (t, 3H).

E. Z. 4 (S) -ZW, 4, 4 (Z) „77-4-71-7 (carboxymethyl) thio7“ 2-hexadecenyl7 “4-hydroxycyclohexanecarboxylic; 77 ²⁰ -1.8 ° (c 0.97, chloroform). ¹ H NMR (CDClp 300 MHz) - 5.72 (m, 1 H); 5.49 (m, 1 H); 4.26 (d, 1H); 3.16 (m, 2H); 2.50-1.17 (33 H); 0.88 (t, 3H).

F. £ 4 (R) -Z "1, 4p, 4 (Z) 77-4-zfl-Z (2-carboxyethyl) thio 7" 2-hexadecenyl7 "4-hydroxycyclohexanecarboxylic acid;

Ζ ^ 7ρ ° + 34.8 ^Ο (c 0.81, chloroform). ^Χ Η NMR (CDOlp 300 MHz) 8

5.63 (m, 1 H); 5.41 (t, 1 H); 3.75 (d, 1H; 2.67 (m, 5 H); 2.09-1.26 (33 H); 0.88 (t, 3 H).

G, £ 4 (S) -Z'l ^ acid, 4 p, 4 (Z) 77-4-71-7 (2-carboxyethyl) thio7 ⁷ -2-h.exadecenyl7 ~ 4 "h.hydroxycycloh. exanocarboxylic;

Ζ% 7§θ-41.4 ° (c 1.26, chloroform). ¹ H NMR (CDClp 300 MHz)

5.63 (m, 1H); 5.42 (t, 3 H); 3.76 (d, 1 H); 2.67 (m, 5 H); 2.09-1.22 (33 H); 0.88 (t, 3 H).

H. acid 71 ⁰⁰ , 4p, 4 (Z) 7-4-71-7 (2-carboxyethyl) -

-tio7-2-hexadecenyl7 “4-hydroxycyclohexanocarboxylic melted at 77 ° -78 ° C. ^X H NMR (CDClp 300 MHz) & 5.63 (m, 1 H); 5.41 (t, 1 H) 3.76 (d, 1 H); 2.68 (m, 5 H); 2.11-126 (33 H); 0.88

-28 · (t, 3 Η).

I. 4 #, 4 (Z) _7 ~ 4-Z'l-zT acid (3-carboxypronyl) -

-tio_y-2-hexadecenyl7-4-hydroxycyclohexanecarboxylic, melted at 71 ° -72 ° C. NMR (OOC1 ₃ , 300 MHz) 5.61 (m, 1 H); 5.36 (t, 1 H); 3.59 (d, 1 H); 2.49 (m, 4 H); 2.25-1.20 (35 H); 0.88 (t, 3 H).

J. / 1 &, 4, 4 (Z) _7-4-Z-1-zT (3-carboxypropyl) -thio_7-2-hexadecenyl _7-4-hydroxycyclohexanecarboxylic acid.

NMR (CDC1 ₃ , 300 MHz) k 5.61 (m, 1 H) $ 5.41 (t, 1 H); 3.69 (d, 1 H); 2.49 (m, 4 H); 2.10-1.22 (35 H); 0.88 (t, 3 H).

K. Zl * ·, 4 ^, 4 (Z) acid 7-4-71 ~ Z ~ Z ~ 3-Z ~ (carboxymethyl) -amino_7-3-oxopropyl _i / -thio_7-2-hexadecenyl_7-4-hydroxy hexanocarboxylic. Η NMR (CDClp 300 MHz) ò 6.85 (m, 1 H);

5.57 (m, 1 H); 5.39 (t, 1 H); 4.27 (m, 1 H); 4.00 (m, 1 H);

3.60 (d, 1 H); 2.90-1.20 (37 H); 0.89 (t, 3 H).

L. acid / loc, 4 · ^, 4 (Z) 7-4-Z 1 ~ Z / Γ3-Z ”(carboxymethyl) -amino _7-3-oxopropyl_7 ~ thio 7-2-hexadecenyl7“ 4-hydroxycyclohexanecarboxylic, melting at about 81.5-82.5 ° C.

NMR (CDCl ₃ , 300 MHz) S 6.80 (s, 1H); 5.63 (m, 1 H); 5.42 (t, 1 H); 4.08 (d, 2 H); 3.70 (d, 1 H); 2.85-2.40 (m, 4 H); 2.10-1.20 (33 H); 0.89 (t, 3 H).

M. Z4 (R) -Z'io <, 4 ^, 4 (Z) J.7-4-Z71-7 (3-amino-3-oxopropyl) -thio_Z-2-hexadecenyl_7-4-hydroxycyclohexanocarboxylic acid, melting at 108 ° -1O9 ° C; Ζ77ρθ ⁺ 48.3 ° (c 0.86, chlorine form). NMR (300 MHz CDClp) E 6.02 (s, 1 H); 5.72 (s, 1 H);

5.60 (m, 1H); 5.45 (t, 1 H); 3.72 (d, 1 H); 2.77 (m, 2H); 2.58 (m, 3 H); 2.15-1.20 (33 H); 0.89 (t, 3 H).

Z ^_ N 4 (R) -zTlíX, 4 ? , 4 (Z) 77-4-ZTlZ ^ (2-carboxyethyl) -tio.7-2-decenil_7-4-hydroxycyclohexanecarboxylic.

-29r t

Example 11

A flask was filled with 315 ml of cyclohexane and a stream of nitrogen was passed through. 2- (1T) entadecenyl) -Z 3 (5) - / ^ 3 ^ 6, 3 (Z), 8 ^ 7 _ / - 1-oxaspiro / ~ 2,5 / -octane-6 was added with stirring methyl carboxylate (397 mg) and diphenyl disulfide 241 mg and the stirred solution was cooled with an ice water bath. A solar lamp was placed over the reaction mixture for 3.6 hours. The solvent was removed in vacuo and the residue was filtered through silica gel with hexane to remove the diphenyl disulfide. Thereafter, an ether wash to obtain a solution of the crude olefin mixture. The ether was removed in vacuo to obtain a yellow oil (cis / trans = 1: 4) which was purified in Prep LC (15% ether / hexane, 2 columns, R ^ = 8 min.) To obtain 120 methyl 2- / 7 (1-nentadecenyl) - / 73 ^, (E), 6p7_7-1-oxaspiro / 2,5_7-octane-6-carboxylate in the form of an oil, 'ή NMR (COCl ^ 300 ΜΗζ) ^ 5.90 (m, 1 H); 5.33 (m, ^{1 H) (J} a, b ^{= 19.1 Hz)? 3.68 (s} ' ^{3 3.18} ( ^d ' ^{1 H)? 2.43 (m} '

H); 2.10-1.20 (32 H); 0.89 (t, 3 H).

The product obtained above was added to 1 ml of methanol in a 5 ml round bottom flask. 0.08 ml of triethylamine was added with stirring followed by the addition of 0.04 ml of methyl 3-mercaptonropionate. After 2 days, the solvent was removed and the crude oil was subjected to rapid chromatography (ethyl acetate / hexane 5%) to obtain 58.3 mg (84%) of / ”1 ^, 4 ^, 4 (E) _7-4-hydroxy-4-Z 1 - / ^ 3-methoxy-3-oxopropyl) -tic ^ -2-hexadecenyl V-cyclohexanecarboxylate in the form of a clear oil. NMR (ODC1 ₃ 300 MHz) S 5.45 (m, 2 H); 3.69 (s, 3 H); 3.67 (s, 3 11); 3.30 (d, 2 H); 2.80-2.20 (m, 5 H); 2.05-1.20 (33 H); 0.89 (t, 3H).

-30Γ f

When the ester described above was hydrolyzed with a base, according to the procedure described in example 9, 4, 3, 4 (E) _7-4-Z-1-Z (2-carboxyethyl) -tic acid was obtained

-2-hexadecenyl_7 ~ 4-hydroxylicolohexanecarboxylic. NMR (300 MHz CDClp) S5.53 (m, 2 H, J _a , _b trans = 15.8 Hz); 3.37 (d, 1H); 2.65 (m, 4 H); 2.15-1.20 (33 H); 0.88 (t, 3 H).

-31 / s

Claims (7)

1.- Process for the preparation of compounds of general formula X 0 r n -CH-C-Y in which n represents an integer between 0 and 2; R represents a straight chain alkyl group containing between 6 and 15 carbon atoms; X represents a hydrogen atom or, when n represents the integer 1 or 2, X can represent an -NH2 group; Y represents oxygen atoms or a hydroxy group, (lower alkyl), -NH ^, -NH (lower alkyl) or -N- (lower alkyl) 2 or a group of general formula -NH-CH-COOH I R 'in which R' represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or a benzyl group; and Z represents a hydroxy group, -0- (lower alkyl), -NH ₂ , -NH- (lower alkyl) or -N- (lower alkyl) ₂ z characterized by the reaction of an epoxide of general formula: 320 in which R has the meaning defined above and Z ¹ represents a group -0- (lower alkyl), -NH ₂ , -NH (lower alkyl), or -N- (lower alkyl) with a derivative of mercapto-alkanoic acid of general formula: X ’0 I II HS- (CH _n ) -CH-C-Y ' 2 n in which n represents an integer between 0 and 2; X 'represents a hydrogen atom or, when n represents the integer 1 or 2, X' can represent a group of general formula Q-NH-, in which Q represents an amine protecting group; Y 'represents a group -O- (lower alkyl), -NH ₂ , -NH (lower alkyl), - N- (lower alkyl) ₂ or -NH- ^ HgY' in which R 'represents a hydrogen atom or a alkyl group having 1 to 4 carbon atoms or a benzyl group and Y 'represents a -0- (lower alkyl) group; in a suitable solvent and in the presence of a base, eventually followed, when Y ', Y' or Z 'represent a -0- (lower alkyl) group, treatment with a strong inorganic base followed by a acidification with a strong acid to obtain compounds in whose general formula Y, Y 'or Z represent an -OH group. 2. A process according to claim 1 for the preparation of compounds of the general formula in which n represents an integer between 0 and 2; R represents a straight chain alkyl group having 6 to 15 carbon atoms; X represents a hydrogen atom or, when n represents 1 or 2, X can represent a -NH ₂ group; Y represents a hydroxy group, -0- (lower alkyl), -NH ₂ , -NH (lower alkyl) or -N- (lower alkyl) ₂ or a group of general formula -NH-CH-COOH in which R 'represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or a benzyl group; and Z represents a hydroxy group, -O- (lower alkyl), -NH ₂ , -NH- (lower alkyl), or -N- (lower alkyl) ₂ , characterized by the reaction of a general formula epoxide in the which R has the meaning defined before, and Z 'represents a group -0- (lower alkyl), -NH ₂ , -NH (lower alkyl) or -N- (lower alkyl), with a derivative of mercapto-alkanoic acid of the general formula: X' 0 I. II HS- (CH-) -CH-C-Y ' 2 n in which n represents an integer between 0 and 2; X 'represents a hydrogen atom or, when n represents 1 or 2, X' can represent a group of general formula Q-NH- in which Q represents an amine protecting group; Y 'represents a group -0- (lower alkyl), - NH ^ -NH (lower alkyl), -N- (lower alkyl) ₂ or -NH-CH-C-Y', ^at Φ ¹³ ·! ^R 'repreR' 0 / · sits a hydrogen atom or an alkyl group with 1 to 4 carbon atoms or benzyl and Y 'represents a -0- (lower alkyl) group; in an appropriate solvent. and in the presence of a base, followed eventually when Y ', Y' or Z 'represent a -0- (lower alkyl) group, treatment with a strong inorganic base followed by acidification with a strong acid to obtain compounds whose general formula Y, Y 'or Z represents an -OH group. 3. A process according to claim 1 for preparing compounds of the general formula in which n represents an integer between 0 and 2; R represents a straight chain alkyl group having 6 to 15 carbon atoms; Y represents a hydroxy group, -NH ₂ , -NH (lower alkyl) or -N- (lower alkyl) _o or a group of general formula -NH-CH-COOH, ² I R 'in which R' represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or benzyl, characterized in that an epoxide of the general formula t is reacted in which R has the meaning defined above, with a derivative of mercapto-alkanoic acid of general formula O HS- CH „-CH _O -C-Y ' 2 n 2 in which n represents an integer between 0 and 2; Y 'represents a group -0- (lower alkyl), -NH ₂ , -NH (lower alkyl), -N- (lower alkyl) ₂ or -NH-N ^ -gY', in which Y 'represents a group - 0- (lower alkyl); in an appropriate solvent and in the presence of a base, followed eventually when Y 'or Y' represent a -0- (lower alkyl) group, treatment with a strong inorganic base followed by acidification with a strong acid for to obtain compounds whose general formula Y or Y 'represents an -OH group. 4.- Process according to claim 1, for the preparation of acid / 4 (R) - / * 1 a4, 40, 4 (2) 7 / -4- / 1- / (carboxymethyl) -thio ./ -2-hexadecenyl_7-4-hydroxy-cyclohexane-carboxylic, characterized by the fact that 2 ™ (1-pentadecenyl) - / 3 (S) - is reacted 3 y3,3 (Z), 6 oi // “- methyl l-oxaspiro / 2.5 / octane-ô-carboxylate -37X with methyl 2-mercapto-acetate, followed by treatment with potassium hydroxide and then acidification with hydrochloric acid. 5.- Process according to claim 1, for the preparation of the acid / γlala..4 P, 4 (Z) Jkf 1- £ (2-carboxy-ethyl) -tio_7-2-hexadecenyl_7-4-hydroxy- cyclohexane-carboxylic, characterized by the fact that 2- (1-pentadecenyl) Z 3 β, 3 (z), 6 hp yl-oxaspiro- / 2.5 _7octane-6-carboxylate is reacted with methyl 3-mercapto-propionate , followed by treatment with potassium hydroxide and then acidification with hydrochloric acid. 6. The process according to claim 1 for the preparation of 4 (R) - / 1, 4 p, 4 (Z) 1 - / * acid (2-carboxy-ethyl / thio _7-2-hexadecenyl J7- 4-hydroxy-cyclohexane-carboxylic, characterized in that 2- (1-pentadecenyl) -f 3 (S) - / * 3/3, 3 (Z), 6 cújy-1-oxaspiro / 2.5 / octane is reacted -ô methyl carboxylate with methyl 3-mercapto-propionate, followed by treatment with potassium hydroxide and then acidification with hydrochloric acid. 7. A process according to claim 1 for the preparation of acid 1 d, 4 p, 4 (Z) 1- / (3-carboxy-propyl) -thio J-2-hexadecenyl / ^- 4-hydroxy -cyclohexane-carboxylic, characterized by the fact that 2- (1-pentadecenyl) 3 (S) - / * 3 p, 3 (Z), 6 to £ Z7 “l” Oxaspiro - / * 2.5 ./octano^ is reacted -methylcarboxylate with Methyl 4-mercapto-butyrate, followed by treatment with potassium hydroxide and then acidification with hydrochloric acid.